Novel thiosemicarbazones derivatives bearing aromatic iodine moiety: Design, synthesis and anti-malarial activity

2.1 Material and reagents

All the reagents and solvents were of the commercial quality and were used without purification. Elemental analysis was performed on a PE-2400 elemental analyzer, the C, H and N analysis were repeated twice. ¹H NMR and ¹³C NMR spectra were obtained with a Bruker AM-400 spectrometer with chemical shifts reported as ppm (in DMSO-d₆, TMS as internal standard). Melting points were determined by an X-6 micro-melting point apparatus and were uncorrected.

2.2 General procedure for the preparation of 4-(p-iodophenyl)-3-thiosemicarbazone derivatives (4a–4e)

The synthetic routes of the target compounds 4a–4e were shown in Scheme 1. In a typical procedure (Hodgkins and Reeves, 1964). Aromatic iodine 1 (21.9 g, 0.1 mol) was dissolved in the minimum amount of benzene and treated with 7.0 mL of carbon disulfide and 16 mL of triethylamine in ice bath, then the solution filtered to get the solid, which was then dissolved in 90 mL of chloroform. A mixture of 15 mL of triethylamine and 10.2 mL of ethyl chlorocarbonate was added dropwise, followed by stirring for 1 h. The chloroform solution was washed with 3 mol L⁻¹ HCl and water, respectively, and dried over sodium sulfate, then evaporated in vacuum to dryness to get crude solid, which on recrystallization with ethanol gave 2. Compound 2 (26.1 g, 0.1 mol) was dissolved in minimum amount of ethanol, and then was dropped to hydrazine hydrate (24 g, 0.4 mol) at ambient temperature. A white solid was separated, which was washed and dried to give 3. Equimolar quantities of thiosemicarbazones 3 and difference aldehydes were mixed in boiling ethanol for about 1–2 h, then solution was concentrated, the solid was filtered and recrystallized with ethanol and dried to give 4a–4e.

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Scheme 1

The synthetic routes of the target compounds.

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All the target compounds were pale yellow solid and stable at room temperature, insoluble in water and readily soluble in DMF and DMSO.

2.3 In vivo in mice anti-malarial study

The biology activities of the target compounds were evaluated against malaria parasite according with the standard test procedures (WHO standard).

3.1 Synthesis of 4-(p-iodophenyl)-3-thiosemicarbazone derivatives and characterization

Firstly, aromatic iodine 1 was treated with carbon disulfide and chloroform to obtain isothiocyanate 2, and coupling reactions with hydrazine hydrate to give thiosemicarbazones 3. Then the title compounds 4a–4e were successfully obtained using difference aldehydes as reagent. Compounds 4a–4e were characterized by ¹H NMR, ¹³C NMR and elemental analysis. All results are in full agreement with the proposed structures. For example, the singlet signal at 8.06 ppm (CH⚌N) and the signal at 6.08 ppm (OCH₂O) of ¹H NMR spectra suggest that compound 4e is consistent with its structure. The results of elemental analyses are in good agreement with those calculated for the suggested formula. The melting points are sharp indicating the purity of these compounds.

3.2 Anti-malarial activity

The biology activities of the target compounds were evaluated against malaria according to the standard bioactivity test procedures (WHO standard). The results were summarized in Table 1. From Table 1, we could find that these compounds showed significant anti-malarial activities in the four-day suppressive in vivo test in mice. At concentrations of 3, 9 and 27 mg/kg of mouse per day, in contrast, compound 4e produced the highest activity against malaria. For anti-malarial activity, structural variation between compounds 4a and 4b results in remarkably different activity. The only structural differences between 4a and 4b are the types of substituents at C-10. Compound 4a contain hydroxyl group moiety at C-10, while 4b has a N(CH₃)₂ group moiety at C-10. This hydroxyl group appears to be particularly responsible for anti-malarial activity. Compounds 4a, 4c and 4d, which contain hydroxyl group moiety at C-10, while 5 has 1,3-dioxolane ring on C-9/C-10 seemed to be much more effective in terms of anti-malarial activity. Furthermore, Compound 4e inhibited the growth of the malaria parasite with the respective percentages: 88.1%, 90.7% and 92.6%. The corresponding values for 5e at the same concentrations were 58.0%, 74.8% and 77.0%, respectively. It was worth noting that the thiosemicarbazones of aromatic iodide analog showed improved biology activities to some extent over aromatic chloride counterparts against malaria, which might be contributed by the introduction of iodine atom in benzene.